The present invention relates to stable coatings for delivering chlorhexidine gluconate.
Chlorhexidine digluconate (commonly known as xe2x80x9cchlorhexidine gluconatexe2x80x9d) is an antimicrobial that is useful for various applications, particularly in the oral environment. Specifically, chlorhexidine gluconate in dental rinses has been clinically proven to reduce gingival inflammation and bleeding. The disadvantages to delivering chlorhexidine gluconate in a rinse are bad taste and staining. Chlorhexidine gluconate is known to decompose to form para-chloroaniline, which is highly toxic.
Hill (U.S. Pat. No. 5,098,711; WO 95/30404; U.S. Pat. No. 5,165,913; U.S. Pat. No. 4,911,927) describes floss coating compositions with chlorhexidine gluconate. The compositions of Hill contain a surfactant and a coating substance that is insoluble in the surfactant. Optionally, the compositions may contain a humectant like glycerin or polyethylene glycol. In Hill""s examples, chlorhexidine gluconate is formed in situ by heating gluconic acid and chlorhexidine free base at high temperature.
Simionato et al (AU 9,464,534) describes putting chemotherapeutic agents in a floss coating composition that contains an emulsifiable wax.
Bowen (U.S. Pat. No. 5,603,921) describes dental floss coating compositions that contain chlorhexidine gluconate and a 2/1 ratio of polyethylene glycol (PEG) 3350/PEG 1000, which are solids at room temperature.
Devices, coating compositions and methods for preparing coating compositions are provided whereby stable chlorhexidine gluconate may be delivered to the oral environment from an essentially non-aqueous system. The coating comprises chlorhexidine gluconate and a Solubilizing Glycol. The coating additionally comprises a modulus-enhancing component to give proper handling properties. The coating does not contain more than 200 ppm of para-chloroaniline after four weeks at 45xc2x0 C.
As noted above, it is desirable to deliver chlorhexidine gluconate (xe2x80x9cCHGxe2x80x9d) to the oral environment. To date, however, systems have not been adequate to deliver CHG in a format other than in an aqueous rinse in a manner that would also provide stability. CHG degrades to toxic byproducts in a non-aqueous environment, including para-chloroaniline (xe2x80x9cPCAxe2x80x9d) a suspected carcinogen. It is therefore surprising to find that a non-aqueous composition (i.e. having less than about 2% water by weight) may be formulated for stable delivery of CHG to the oral environment.
Non-aqueous coatings of the present invention provide significant advantages in the delivery of CHG. Because the coating does not contain water, it is more shelf-stable for longer term storage since there is no water loss or requirement for special packaging to retain water in the coating.
Coated CHG delivery devices of the present invention, as compared to aqueous rinses, are useful particularly for delivering chlorhexidine gluconate interproximally and subgingivally, where it is needed to treat gingivitis. Site specific delivery of chlorhexidine gluconate from a device, as in the present invention, minimizes the discomfort associated with the bad taste of chlorhexidine gluconate and reduces tooth staining by reducing contact of the chlorhexidine gluconate with the facial tooth surfaces.
The device of the present invention is any device suitable for physical delivery of CHG to the oral environment, and most preferably a device suitable for delivery to interproximal and subgingival surfaces of the oral environment. Such devices include dental floss, dental picks, and dental tape. Additionally, the device may be a dental packing material, such as a fiber. Other embodiments include periodontal membranes.
Dental floss coated with the compositions of the present invention is highly advantageous, because it slips easily between the teeth and yet is easy to hold in the user""s hands.
The coating of the present invention comprises chlorhexidine gluconate. CHG may be commercially obtained from many manufacturers, but typically only in an aqueous format. It is important to properly handle aqueous CHG, particularly as to exposure to high temperatures, to retain stability when formulating the non-aqueous compositions of the present invention, as will be described in more detail below.
Preferably, the coating of the present invention comprises between about 0.1% and 15% of CHG by weight. More preferably, the coating comprises 0.5-10%, and most preferably, the coating comprises 1-5% of CHG by weight.
For purposes of the present invention, a xe2x80x9cSolubilizing Glycolxe2x80x9d is a glycol that provides a clear solution when mixed with CHG in the glycol/CHG ratio to be used in the ultimate coating composition. This evaluation of solution clarity is made to a mixture containing only CHG, glycol and any residual water, after water has been removed to a level less than about 10% and the solution is at room temperature (about 21xc2x0 C.). It is understood that mechanical mixing under heat as high as 100xc2x0 C. may be employed to mix the CHG with the glycol, but that the evaluation will be made after the solution has cooled and allowed to stand for 60 minutes.
Examples of glycols capable of dissolving and stabilizing chlorhexidine gluconate are glycerin, sorbitol, polyethylene glycol (preferably of molecular weight between about 200 and 600), polyglycerols (e.g. triglycerol, hexaglycerol and decaglycerol), and propylene glycol. These glycols may be used separately or in combination. It will be recognized that while individual glycols may not provide the desired clear liquid, mixtures of glycols may be suitable to be collectively used as the Solubilizing Glycol.
Solubilizing Glycol is preferably present in the coating in an amount such that the ratio of Solubilizing Glycol to chlorhexidine gluconate by weight is 0.2-200. More preferably the ratio of Solubilizing Glycol to chlorhexidine gluconate by weight is 0.5-7, and most preferably, the ratio is 1-5.
The modulus-enhancing component is any material that provides the desired final modulus properties for the coating, such that it will have the proper tackiness and material delivery properties of a coating. Thus, the coefficient of dynamic friction (ASTM D3247) is preferably less than 2.0 and more preferably less than 1.0. The elastic modulus, Gxe2x80x2, should be greater than 10,000 and preferably greater than 100,000 dynes/cm2 at a frequency of 1 rad/sec and at room temperature. The ratio of the viscous modulus, Gxe2x80x3, to Gxe2x80x2 (or tan delta) should be less than 0.8 and preferably less than 0.5 at a frequency of 1 rad/sec and at room temperature.
Examples of modulus enhancing components include surfactants that contain both (a) hydrophilic group(s) capable of dispersing chlorhexidine gluconate and a glycol, and (b) an alkyl group(s). Preferably the alkyl group makes up 3 to 75% by weight of the modulus-enhancing component, and more preferably 5 to 60 wt. %. Examples of such preferred surfactants include polyglyceryl alkyl esters and ethers, ethoxylated polyhydric alcohol alkyl esters, and polyoxyethylene alkyl ethers or esters. These surfactants may act to bind individual fibers of a dental floss together, or may help in the formulation process to assist in making certain ingredients compatible in the overall coating formulation. Surfactants may be particularly beneficial in assisting wax to be compatible with the rest of the coating composition.
Alternative modulus enhancing components include waxes, poly-n-vinyl pyrrolidone, crystalline fatty alcohols, paraffins, polyethylene oxides having molecular weight greater than about 900, hydroxypropyl cellulose and cellulose derivatives. Preferably, these materials are soluble in or emulsifiable with glycerin.
Wax is particularly preferred in the tooth floss embodiment when it may be desirable to help bind the floss fibers together and to improve the floss handling characteristics. Examples of waxes are microcrystalline wax and beeswax. Alternatively, floss coatings may be formulated such that the fibers are not bound together.
Compositions of the present invention may additionally comprise appropriate adjuvants such as colorants, stabilizers, preservatives, flavorants, sweeteners, additional medicaments (such as fluoride and desensitizers), cleansers and the like.
Salts, acids, and bases that are not to be present in the compositions of the present invention are limited in amount such that they cannot interact with more than 50% of the CHG in the device. In other words, the coating has less than 0.50 molar equivalents of deleterious quantities of salts, acids, and bases that would react with chlorhexidine gluconate based on the amount of chlorhexidine gluconate in the composition. Preferably no more than 0.10 molar equivalents of salts, acids, or bases based on the amount of CHG are in the formulation. More preferably no more than 0.01 molar equivalents, and most preferably no more than 0.001 molar equivalents of salts, acids, or bases based on the amount of CHG are in the formulation.
Examples of salts, acids, and bases that are not to be present in the compositions of the present invention include water soluble or emulsifiable species of the following: carboxylic acids and polycarboxylic acids and their salts (with the exception of gluconic acid and its salts), sulfates, sulfonates, phosphates, phosphonates, acetates, sulfosuccinates, including anionic surfactants utilizing these as hydrophilic groups. Halides, nitrates, hydroxides, carbonates, oxalates, thiocyanates, sulfides, chromates, arsenates, cyanides, chlorates, and iodate salts are also a potential concern. As a general principle, it is desirable to avoid strong acids and strong bases and anionic surfactants, because each of these species tends to adversely react with chlorhexidine gluconate.
It is also desirable that the pH of the composition be maintained between 5 and 8 to provide a more stable system. Due to the anhydrous nature of the material of this invention a convenient method for assessing the relevant pH of the compositions is to dissolve or suspend the material at a 5 to 10% weight basis in pH neutral water and measure the resulting pH.
The stable coating composition of the present invention is made by first mixing aqueous chlorhexidine gluconate with a glycol and optionally with the modulus-enhancing component to form a mixture that is substantially free of deleterious quantities of salts, acids, and bases that would react with the chlorhexidine gluconate. Water is then removed at a temperature less than 100xc2x0 C., more preferably less than 80xc2x0 C. and most preferably less than 60xc2x0 C. Preferably, the water removal operation is conducted under vacuum. The composition is then ready for final formulation (if not all materials in the final formulation have not already been added) and coating on the device. Alternatively, the removal of water may be undertaken after coating a water-containing formulation on the device. While brief periods of exposure of the composition to temperatures above 100xc2x0 C. may be allowed, extended exposure to high temperature may be seriously deleterious to the stability of the coating composition. It has therefore been surprisingly found that temperature control of the water removal process is extremely important in the production of stable coatings of the present invention.
In an alternative preparation technique, the aqueous chlorhexidine gluconate may be freeze-dried, thereby removing substantially all water from chlorhexidine gluconate in a rapid manner. The thus freeze-dried chlorhexidine gluconate may then be mixed with glycol. The modulus-enhancing component and/or other desired ingredients of the final formulation may be mixed at the same time as the glycol, or as a subsequent formulation operation. The composition is then ready for final formulation (if necessary) and coating on the device.
It particularly desirable to conduct the water removal step under vacuum. This condition allows for use of lower temperatures than would otherwise be required, shorter times at elevated temperatures, and further may facilitate removal of undesirable volatile degradation products or impurities.
The compositions may be coated onto the intended device using appropriate coating techniques, such as dip, melt, extrusion or spray techniques. To facilitate this coating process, it is preferred to formulate the composition such that the melt point of the total composition is about 40-60xc2x0 C., and more preferably about 40-50xc2x0 C.